INTRODUCTION

The crown-root ratio is an important consideration in orthodontic and prosthodontic treatments.¹ The overall tooth length (crown height and root length) determines the orthodontic force that can be transmitted during orthodontic treatment, and it is involved in the pattern of tooth movement.^2–4 Furthermore, the identification of the root length at the time of orthodontic diagnosis and treatment is essential.⁵

Both environmental and genetic factors can lead to dental variation.⁶ The inheritance patterns of dental variation have been studied, and it has been suggested⁷ that genetic factors are strongly involved in dental variation. However, there is limited knowledge about human genetic variants associated with common dental variations.⁷ Studies⁸ on human crown variation have linked the shovel-shaped incisor, a characteristic feature of Mongoloids, with EDAR variants. Others have also shown that the mesiodistal width of the human crown is associated with EDAR,⁷ WNT10A,⁹ and PAX9.¹⁰ WNT10A is also associated with the distolingual cusp in the lower second premolars, the fifth cusp in the upper first molars, and the hypoconulid in the lower second molars.⁹ However, no human genetic variant has been reported to be associated with tooth length.

The human growth hormone receptor (GHR) gene, located at 5p13.1-p12, measures about 87 kb and comprises 10 exons.¹¹ The major function of growth hormone (GH) is in the promotion of postnatal growth¹² through the GH/GHR/insulin-like growth factor I signaling axis, as identified through the study of GHR knockout mouse phenotypes.¹³ GHR also plays a role in maintaining proportional skeletal growth,¹³ with GHR mutations responsible for Laron syndrome (GH insensitivity syndrome) and idiopathic short stature.¹⁴ Treatment of Laron syndrome with insulin-like growth factor I tends to induce dental maturation, particularly in younger patients.¹⁵ In patients with idiopathic short stature, dental age is rarely affected and is less responsive to GH,¹⁶ yet tooth eruption patterns are identical to those of patients with normal GH secretion.¹⁶ Other studies have shown that GH secretion is associated with both tooth eruption and maturation^17,18 and that rodent cellular cementum also relies on GH.¹⁹

Given the clear role of GH in skeletal growth and development, in the present study, the relationship between tooth length and two gene variants of GH (rs6184 and rs6180) were examined in Japanese subjects.

MATERIALS AND METHODS

Tooth Size Measurements

CBCT images were acquired using a dental cone-beam X-ray CT scanner (CB MercuRay, Hitachi Medico Technology, Tokyo, Japan) or a KaVo 3DeXam (KaVo, Biberach, Germany) at the radiology department of the university hospital. The scanning conditions were 100 kVp, 10 mA, F-mode 512 slices/scan (slice width: 377 mm), and 9.6-second acquisition time. Data obtained were reconstructed using the open-source OsiriX medical image processing software (Pixmeo, Geneva, Switzerland; www.osirix.viewer.com) and exported using the DICOM format to a MacBook Pro personal computer (Mac OsX El Capitan 10.11.6 Apple, Cupertino, Calif). The difference in measurement between the two models of CBCT was evaluated using the method reported by Katayama et al.²⁰ The difference was small and nonproblematic.

For the measurement of tooth length, CBCT images were oriented using multiplanar reconstruction, and teeth were measured using a modification of the method described by Abeleira et al.²¹ After each target tooth was positioned following the method of Abeleria et al.,²¹ the crown height (CH) and root length (RL) were measured in the coronal plane. To measure CH, a perpendicular line was drawn from the line between the buccal and palatal limits of the cementoenamel junction to the incisal edge or tip of each cusp in the case of the premolars and molars. RL was measured by drawing a perpendicular line from the line between the buccal and palatal limits of the cementoenamel junction to the apex of the tooth or each root, respectively. The distance between the incisal edge or cusp and the root apex was measured in central incisors (upper [U]1, lower [L]1), lateral incisors (U2, L2), and canines (U3, L3). The distance between the buccal cusp and buccal root apex was measured in the premolars (U4, U5, L4, L5) when it had two roots. The distances between the mesiobuccal cusp tip and the mesiobuccal root apex (U6M, U7M), between the distobuccal cusp tip and distobuccal root apex (U6D, U7D), and between the mesiopalatal cusp tip and palatal root apex (U6P, U7P) were measured in the upper molars. In the lower molars, the distances between the mesiobuccal cusp tip and mesial root apex (L6M, L7M) and between the distobuccal cusp tip and distal root apex (L6D, L7D) were measured. Figure 1 describes these measurements. CHs and RLs were averaged between left and right sides for each tooth. If the tooth on only one side was measurable, the value of this tooth was used. Where teeth on both sides were unable to be measured, the value was considered missing. Overall tooth length (C+R) was calculated by adding CH and RL. The crown-to-root ratio (C/R) was calculated by dividing CH by RL.

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The measurements were performed by one researcher (YH). To investigate intraoperator error, 25 subjects were chosen randomly and remeasured in separate sessions at a 2-week interval under identical conditions. Measurement error was estimated according to Dahlberg's formula (S2 = ∑d2/2n).^22,23

RESULTS

The mean values and standard deviations for each tooth measurement are shown in Table 1. The measurement error estimated by Dahlberg's formula was 3% or lower for each measure, indicating sufficient reproducibility. The allele frequencies of the GHR variants were 46.6% and 8.1% for rs6180 and rs6184, respectively (Table 2). The multiple regression analysis revealed that the GHR rs6184 variant was associated with the tooth size of U2 RL, U3 RL, C+R, and L2 RL (P < .05) (Table 3).

Table 1.  Means and Standard Deviations (SDs) of the Measurements from Cone-Beam Computed Tomography (CBCT)^a

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Table 2.  Single Nucleotide Polymorphisms Examined in this Study

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Table 3.  Association Tests Using Multiple Regression Analyses^a

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DISCUSSION

In the present study, the relationship between GHR variants (rs6180 and rs6184) and tooth length was examined using CBCT imaging in Japanese healthy subjects. The GHR gene variant rs6184 was associated with the root lengths of U2, U3, and L2. This is the first study reporting a genetic variant associated with human tooth lengths.

Growth hormone is involved in the maturation and formation of teeth. In pituitary dwarfism, tooth size or arch dimensions are smaller than normal,¹⁶ whereas in pituitary gigantism, patients demonstrate premature tooth eruption and hypercementosis.¹⁹ Smid et al.¹⁹ previously reported that in the mouse, cellular cementum relies on the presence of GH, confirming the results of Becks and colleagues,²⁴ who found that daily injections of GH in rats for several months likely resulted in hypercementosis in the molar teeth. Indeed, the GHR mutation causes delayed tooth maturation and eruption in patients with Laron syndrome and idiopathic short stature, which can be improved with GH supplementation.^15,25 Previous studies have found associations for GHR with the mandibular ramus height,^14,26,27 mandibular growth during early childhood,²⁸ and the distance between the left and right coronoid processes.²⁹ Several groups^30–32 have hypothesized, but not tested for, an association between tooth length and mandibular morphology. More comprehensive and larger-scaled studies will be needed to validate the complete associations of GHR variants with various aspects of the jaw.

The cell sensitivity to GH and the site of GH action are closely coordinated to affect the formation and eruption of teeth.³³ At sites of new matrix formation, cementoblasts and odontoblasts displayed expression specifically against GHR, although cementocytes and mature odontoblasts at later stages of tooth development did not.³³ The functional mechanism by which the GHR gene variant identified may be responsible for tooth length is still unclear.

In this study, the association of the root lengths and tooth length with GHR variants was investigated in CBCT images in a large number of subjects and compared with the results of a number of previous reports.^21,34–40 A maximum 8.4-mm difference in U3-R was found between the current cohort and Finnish males,^34,35 suggesting that the crown and root lengths in Japanese may be smaller than those in Europeans, excluding those of U1, U2, L1, and L2. Interpopulational and regional differences in the crown width are well known.^41–45 With larger crown widths in Africans, intermediate widths in Asians, and much smaller widths in Europeans, these variations in the crown width are different from those in the crown and root lengths. ⁴⁴ In addition, a recent report⁴⁵ comparing crown width in Japanese from the 1940s, the 1980s, and the 1990s suggests that changes in nutritional condition and dietary habits may have affected crown width. As described above, changes over time and regional differences in crown length and root length may be observed. Moreover, the current results were not significant when a multiple testing correction was implemented. Further studies with a larger sample size are needed to validate the result and to better understand the relationship between the human genome and dental variation.

CONCLUSIONS

• GHR rs6184 variant is associated with root length (U2 RL, U3 RL, L2 RL) and overall tooth length (U3 C+R).

• GHR rs6180 variant is not associated with crown height, root length, overall tooth length, or crown-to-root ratio.